Functional and structuraladaptation in the

central nervous system

Anthony Holtmaat

The Central Nervous System

The Central Nervous SystemControls and Responds to Body Functions and

Directs Behavior

The brain is the body’s most complex organ. 2% of the total body weight

There are a hundred billion neurons in the human brain.1011 neurons (compare to for example less than 1 million in honey bee)

Each neuron communicates with many other neurons to form circuits andshare information.1000-10.000 synapses per ‘typical’ neuron.

Proper nervous system function involves coordinated action of neurons inmany brain regions.

The nervous system influences and is influenced by all other body systems(e.g., cardiovascular, endocrine, gastrointestinal and immune systems).

This complex organ can malfunction in many ways, leading to disorders thathave an enormous social and economic impact.economic impact.

Brain disorders are an enormousburden on our society

Sensory stimuli are converted into electrical signals.

Action potentials are electrical signals carried along neurons.

Synapses are chemical or electrical junctions that allow electricalsignals to pass from neurons to other cells.

Changes in the amount of activity at a synapse can enhance or reduceits function.

Communication between neurons is strengthened or weakened by anindividual’s activities, such as exercise, stress, and drug use.

All perceptions, thoughts, and behaviors result from combinations ofsignals among neurons.s among neurons.

Neurons communicate using both electricaland chemical signals.

Cerebral hemisphere(Neo)cortex

DiencephalonMidbrain

Pons

Medulla

Cerebellum

Spinal cord

Information gatesFinal processorHigher thinking

Integration

Autonomicfunctions

HighwayReflexes

The cerebral cortex20 billion neurons; 77% of brain volume; 2.500 cm2

Cortical neuronal layers

I

II/III

IV

V

VI

Cortical cytoarchitecture

Layer III - external pyramidal cell layer, send axonsto other parts of cortex

Layer I - molecular layer, dendrites, axons

Layer II - external granule cell layer, small neurons

Layer IV- internal granule cell layer, granule cellsthat receive input from deeper brain regions orother superficial cortical layers

Layer V - internal pyramidal cell layer, larger cellsthan layer III, output, feedback projections

Layer VI - polymorphic or multiform layer,heterogeneous cells

White matterPS. There are manyprojection neurons aswell as interneurons

The brain develops with enormous speed overweeks to months to its final size, and then itscircuits are optimized over many years

Ligand Receptor/ligand Attraction/repulsion

Short-range(contact mediated)

Slit Robo RepulsionN-CAM N-CAM AttractionECM adhesion prot Integrins AttractionEphrins Eph receptors Repulsion

Long range(diffusible ligand)

Netrin DCC AttractionSemaphorins Neuropilins RepulsionSlit RepulsionNetrin Repulsion

Examples of short- and long-rangechemoattraction and chemorepulsion

EGFP

Sema3A

Repulsion assayCollapse assay In vivo

EGFP

EGFP-Sema3A

Example of axon guidance duringneuronal development

Critical periods•A critical period is a limited time in which a event can occur,usually to result in some kind of transformation•A critical period in developmental psychology and biologyrepresents early stages in life during which a system is highlysensitive to environmental stimuli, affecting the way it develops•The effects of the lack of appropriate stimuli during a criticalperiod might have long lasting and irreversible effects on thefunctioning of the system•Different components of a neuronal circuit (cell types, nuclei,layers) can have distinct critical periods•Activity-dependent or experience-dependent development ofsensory systems•The most well-known examples are: binocular vision (between oneand two years for humans); hearing; parental imprinting; bird song;first language acquisition vs second language acquisition

Muscle contraction

Touch

Ouch!!!

He hurt me;I want tokick him..

The cerebral cortex governs higher mental functions

•Four lobes, named after after the skull bones that encase them•Frontal - planning, movement•Parietal - somatic sensation, body awareness•Occipital - vision•Temporal - hearing; learning, memory, emotion (hippocampus, amygdala)•About 1010 (10 billion) neurons, and 1014 (100 trillion) connections

The cerebral cortex - cognitive functions

Lateral sulcus

Precentral gyrus

Lateral sulcus Lateral sulcus

Postcentral gyrus

Korbinian Brodmann (1868-1918) : cyto-architecture of the brain

motor skillssomatosensory

hearing

visionshort term memory,decision making

The cerebral cortex has functionally distinct regions

The body surface is functionally represented in thecortex in a topographical fashion

Homunculus

Importance of the modality~ Size of the representation

Marshall, Penfield, Woolsey

from Kandel, Schwartz and Jessell

Wilder Penfield (1891-1976)

Somatosensory map Motor map

The body surface is represented in the cortex in atopographical fashion in sensory and motor cortex

Marshall, Penfield, Woolsey

Spinal Cord Lesion

Brain Tumor

Alzheimer’sStroke

Amyotrophic lateral sclerosis

Creutzfeldt-Jacob disease

Huntington’s

Multiple Sclerosis

Parkinson’s

Spinocerebellar ataxia

Regrowth of damaged neurons in the CNS is very difficultand complicated

Functional recovery after peripheral damage,and more….

Cortical map plasticity can bemaladaptive: Phantom limb sensations

Ramachandran, Taub

A. Stimulation ofthe face elicits

sensation referringto the phantom

limb

B. Referredsensation localizedto distinct areas in

the stump

videohttp://www.youtube.com/view_play_list?p=1EE802FC3F997400&search_query=ramachandran+phantoms+in+the+brain

Jaillard, A. et al. Brain 2005

10 days 4 months 2 years

motor cortex activity upon finger tapping measured with fMRI

patients recovered from stroke

controls without stroke

Cortical map plasticity can be useful:recovery from stroke

Overlaid images of control and stroke patients. Blue is the normalrepresentation of finger tapping, red the adapted response after stroke

Hund-Georgiadis and von Cramon,1999 Exp Brain Res Gizewski et al. 2003 NeuroIamage

Piao playertappingfinger

Controlpersontappingfinger

Functional expansion of motor and sensoryareas after extensive training

Blind personreading Braille

Normal sightedperson readingBraille

The topographic map is functionally adaptive

Merzenich, Kaas, et al

How sensitive are these maps?Do they change in reponse to other types of stimuli?Does this happen in other species as well?

Plasticity of motor areas after lesions•The functional organization of theprimary motor cortex changes aftertransection of the facial nerve (cranialnerve VII)•Areas devoted to forelimb andperiocular control have increased, andexpanded into the area previouslydevoted to whisker control

Each area has its own very detailed map

The maps are plastic - expansion

•Somatosensory cortex, handrepresentation•Extensive training - expansion ofthe representations•Repeated use of the tip of the digits2, 3, and occasionally 4 - substantialenlargement of the corticalrepresentation of the stimulatedfingers after training•After training the number ofreceptive fields in the distal digits 2,3 and 4 is larger than before training

The maps are plastic - reduction

•Fusion of the digits -simplification of therepresentations•Areas that were distinct nowcommonly respond to both digits•The common area remainsimmediately after seperation ofthe digits - the changes occurcentrally

Special case:The whisker to cortex projections

The representation of the snout in therodent SI is very large

The mouse and rat barrel cortex

Woolsey, Van der Loos

•The dense neurpil of the projections can be seen by various staining procedures•Whiskers are individually represented in barrel-related cortical columns

Information flows through the (1) trigeminal nucleus (cranial nerve V) inthe brain stem, (2) VPM of the thalamus to the (3) cortex

The whisker to barrelcortex pathway

The layers of the barrel cortex

•Thalamocortical input in layer 4•Layer 5 and 6 are themain output to subcortical somatosensoryand motor areas such as thalamus, pons and striatum

•Formation of the barrel pattern by thethalamocortical afferents•No pattern at one day after birth (A)•At 2, 3 and 4 the patterns becomesincreasingly clear

•Deprivation, genetic lesions, ortransections of the peripheral nerve duringthe thalamacortical ingrowth disturbs thethe formation of barrel patterns•Later in life this has no effect

Activity dependent development of thebarrel cortex

Critical periods in the visual cortex

•Closure of one eye at 2 weeks(monkey)•Columns of the closed eye arenarrower than normal•Arborization of geniculate axons isreduced

Ocular dominance distribution in normalmonkeys

•Right eye closed at21 days for 9 days•Subsequent 4 yearsof vision has notrestored the originalresponse distribution

Plasticity in the auditory cortex aftermisguiding input

Cortical plasticity duringadolescence and adulthood

Assessment of barrel cortex plasticity

•Increased responses of neurons in the barrelsneighboring the spared barrel•The spared whisker recruits neurons from thedeprived barrels

Plasticity in the barrel cortex

•Plasticity in the barrel cortex becomes apparent after whisker clipping•Clipping of whisker but leaving one or more intact will cause increases in therepresentation of the spared whiskers

What are the cellular correlates of this typeof functional plasticity?

Feldmeyer et al. J. Phys. 2006

Long range Flexible potential connectivitye.g. new connections through dendritic or axonal sprouting

Short range Fixedpotential connectivitye.g. generation of new

synapses through spineor bouton growth

Local Fixedconnectivity

e.g. synapse growthor

changes intransmitter

release/receptorcomposition

Three type of changes that could correllate withexperience dependent plasticity?

" . . . it is almost impossible to do experiments whose conditions approach thenormal physiological state, during which the changes in position and form of theneuronal arborizations could be fleeting and erased"

Challange : visualization and the dimension time

Santiago Ramon y Cajal, 1899, on the motility ofdendrites and spines.

Solution1Thy1-XFP transgenic mouse lines:

expression in pyramidal cells

GFP-M YFP-H

Solution 2: 2-photon absorption microscopyexcitation only in the focal volume

Two-photon excitation Localization of excitation

absorption ~ (exc. intensity)280% of absorption

in focal volume

nIR green

Reviews:

Denk & Svoboda, Neuron 1997; Zipfel, Williams & Webb, Nat Biotech 2003

Helmchen and Denk, Nature Methods 2005; Svoboda and Yasuda, Neuron 2006

from Zipfel et al, Nat Biotech 2003

single photon excitation two-photon excitation

blue

absorption ~ exc. intensity

Single-photon excitation

S1

skull

dura

cover-glass

Solution 3: Cranial window

Revisitingdendrites and spines

Trachtenberg et al 2002. Nature; Holtmaat et al 2005. Neuron; Grutzendler et al 2002. Nature

0 4 8 12 16 20 24 280

1

Time (days)

Surv

ival

frac

tion

Transientfraction

Persistentfraction

0.8

0.6

0.4

0.2

At least two classes of spines (L5B neurons):

1. Persistent spines: large, stable spines

2. Transient spines: thin spines that appearand disappear

Transient and persistent spines in theadult neocortex

Experience-dependent plasticity in barrel cortex

Trim all whiskersexcept D1

Fox, Simons, Ebner, Diamond et al

Representations change upon peripheral manipulations

α

β

γ

δ

E1

C1

B1

A1

D1

Trimmed

SparedDeprived

Control

α

β

γ

δ

E1

C1

B1

A1

D1

0 12 16 20 24 2884Imaging day

Control or Trimmed

5 µm

day0 8 12 2816 20

Inducing experience-dependent plasticitycombined with long-term imaging

0

0.1

0.2

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0-4 4-8 8-12 12-16 16-20 20-24 24-28

frac

tion

of tr

ansi

ent s

pine

s

Time (days)control trimmedFrac

tion

Pers

iste

nt S

pine

s G

aine

d

0

0.05

0.1

0.15

0.2

0.25

Frac

tion

Pers

iste

nt S

pine

s Lo

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control trimmed0

0.05

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0.15

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0.25

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100µm

PND 69 PND 165***

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Barrel C1 Barrel D1

SAMPLE SELECT

deprived sparedspared

activity changedue to whisker

clipping

trimming

Experient dependent spine and synapse formation inthe barrel cortex could underly map plasticity

Is this a general phenomenon?

Does it work for real lesions?

Structural plasticity: chaning of spines,axonal boutons and synapses

Structural plasticty after retinal lesions

And what about central nervous system lesions?

Plasticity after stroke in mice

•Stroke in the fore limb representation resultinitially in a silent area•The receptive fields expand: cells in the hindlimb area start to respond to both, fore andhind limb

END